title: The role of ABCA1 gene sequence variants on risk of Alzheimer's disease.
abstract: The ATP-binding cassette, sub-family A, member 1 gene (ABCA1) is a candidate risk gene for late onset Alzheimer's disease (LOAD) as a consequence of its role in cholesterol transport and metabolism, which is implicated in LOAD risk. ABCA1 has been shown in mouse models to enable the clearance of amyloid-β peptide from the brain, through its role in the lipidation of apolipoprotein (APOE). Although recent large scale genome wide association studies (GWAS) have failed to find significant associations with common genetic variants in this gene and LOAD, rare variants in ABCA1 have been shown to influence plasma high-density lipoprotein cholesterol levels. Using next generation sequencing of pooled DNA samples, we sequenced all the coding regions of ABCA1 in 311 LOAD cases and 360 control individuals drawn from the Greek population to identify low frequency non-synonymous variation. There were a significantly higher proportion of rare non-synonymous variants in control individuals compared to AD cases, suggestive of a protective effect. These findings provide new evidence of an effect of ABCA1 variants on AD risk. In addition they highlight the importance of high throughput sequencing in the identification of rare variation undetected by GWAS, but with the potential to have a strong effect on risk of LOAD.
authors.affiliation: Department of Neuroscience, Institute of Psychiatry, King's College London, London, UK QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Lupton
authors.forename: Petroula
authors.initials: P
authors.lastname: Proitsi
authors.forename: Kuang
authors.initials: K
authors.lastname: Lin
authors.forename: Gillian
authors.initials: G
authors.lastname: Hamilton
authors.forename: Makrina
authors.initials: M
authors.lastname: Daniilidou
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1
keywords: ATP-binding cassette sub-family A (ABC1) member 1; ATP-binding cassette transporters; Alzheimer's disease; candidate gene analyses; cholesterol; genetic association studies; high-throughput nucleotide sequencing